God took care to hide that country till He judged His people
ready-Then He chose me for His whisper and I've found it, and it's yours.

rudyard kipling

Inmost
of the great scientific discoveries there has been one part deliberate
research and one part luck, Pasteur, a man of unusual firmness of purpose
who sought the truth with a combination of pure reason and experiment, was
sometimes helped by Chance. He was called upon to deal withad
hocproblems
which later were to lead him to general conclusions. If he had not been
appointed to a professorship at Lille, if the distillers and brewers of the
neighbourhood had not gone to him for advice, he might perhaps not have come
to take an interest in fermentations, though, his genius being what it was,
he would have discovered something else. Fleming had for a long time been
hunting for a substance which should be able to kill the pathogenic microbes
without damage to the patient's cells. Pure chance deposited this substance
on his bench. But, had he not been waiting for fifteen years, he would not
have recognized the unknown visitor for what it was. H

Once again, as at the very beginning of his career, he had
just been taking stock of the weapons which medicine could employ against
the infections. The means of defence were woefully inadequate, but he
refused to give up hope. 'At present', he wrote, 'there seems
little chance of finding any general antiseptic capable of killing bacteria
in the blood stream, though there is some hope that chemicals may be
produced with special affinities for special bacteria which may be able to
destroy these in the blood, although they may be quite without action on
other and, it may be, closely allied bacteria.'

He was studying a new antiseptic, mercuric chloride, which
killed streptococci, though, as always, at a degree of concentration which the human body could not tolerate. He put the question
to himself whether, by injecting it into the blood stream in weaker doses,
it might not be possible to achieve a degree of concentration which would
not destroy either the human cells or the streptococci, butmighthave
the effect of making the latter more fragile and, consequently, more
vulnerable to the action of the phagocytes.

His laboratory was still small and encumbered. An
accumulation of culture dishes was piled in apparent disorder, though he
could always find the one he wanted without a moment's hesitation. His door
was almost always left open and any young research-worker in need of some
variety of microbe or of some particular implement was given a warm welcome.
Fleming would stretch out an arm, lay his hand at once on the required
culture, give it to the intruder, and then, usually without uttering a word,
go back to his work. When the air in the tiny room became stifling he would
open the window which looked on to Praed Street.

In 1928 he agreed to contribute an article on the
staphylococci to a vast undertaking —A
System of Bacteriology—
to be published by the Medical Research Council. Some time before this, his
colleague, Merlin Pryce (now Professor Pryce) had, while working with him,
devoted a certain amount of study to some abnormal forms, mutants, of these
microbes.

Fleming, who liked nothing better than to give a helping hand
to the young, wanted to quote Pryce in his article. But the latter had left
Wright's department before he could complete his researches. Being a
conscientious scientist he did not want to publish his results without
verifying them, and his new job gave him insufficient leisure in which to do
this quickly. Fleming, therefore, had to work again over the ground already
covered by Pryce, and set himself to study numerous colonies of
staphylococci. In order to examine these colonies, cultivated on agar in
Petri dishes, he had to lift the lids of the dishes and leave the contents
for some considerable time exposed under the microscope, which meant running
a risk of contamination.

Pryce went to see Fleming in his little laboratory, where he
found him, as usual, surrounded by innumerable dishes. The cautious Scot
disliked being separated from his cultures before he was quite certain that
there was no longer anything to be learned from them. He was often teased
about his disorderly habits.

He was now to prove that disorder may have its uses. With his
rough humour he reproached Pryce for obliging him to re-do a long job of
work, and, while speaking, took up several old cultures and removed the
lids. Several of the cultures had been contaminated with mould — a not
unusual occurrence. 'As soon as you uncover a culture dish something
tiresome is sure to happen. Things fall out of the air.' Suddenly, he
stopped talking, then, after a moment's observation, said, in his usual
unconcerned tones: 'That's funny On the culture at which he was looking
there was a growth of mould, as on several of the others, but on this
particular one, all round the mould, the colonies of staphylococci had been
dissolved and, instead of forming opaque yellow masses, looked like drops of
dew.

Pryce had often seen old microbial colonies which for various
reasons had dissolved. He thought that probably the mould was producing
acids which were harmful to the staphylococci — no unusual occurrence. But,
noticing the keen interest with which Fleming was examining the phenomenon,
he said: 'That's how you discovered lysozyme.' Fleming made no answer. He
was busy taking a little piece of the mould with his scalpel, and putting it
in a tube of broth. Then he picked off a scrap measuring about one square
millimetre, which floated on the surface of the broth. He obviously wanted
to make quite sure that this mysterious mould would be preserved.

'What
struck me', Pryce says,cwas
that he didn't confine himself to observing, but took action at once. Lots
of people observe a phenomenon, feeling that it may be important, but they
don't get beyond being surprised — after which, they forget. That was never
the case with Fleming. I remember another incident, also from the time when
I was working with him. One of my cultures had not been successful, and he
told me to be sure of getting everything possible out of my mistakes. That
was characteristic of his whole attitude to life.'

Fleming put the Petri dish aside. He was to keep it as a
precious treasure for the rest of his life. He showed it to one of his
colleagues: 'Take a look at that,' he said, 'it's interesting — the kind of
thing I like; it may well turn out to be important.' The colleague in
question looked at the dish, then handed it back with a polite: 'Yes, very
interesting.' But Fleming, in no way discouraged by this manifestation of
indifference, temporarily abandoned his investigation of the staphylococci,
and gave himself entirely to studying the surprising mould.

What exactly is a mould? It is one of those tiny fungi,
green, brown, yellow or black, which proliferate in damp cupboards or on old
boots. This type of vegetation results from 'spores' — smaller than a red
blood corpuscle — reproductive organs which float in the air. When one of
them settles upon a suitable medium, it germinates, buds and puts out shoots
in every direction until a soft mass forms.

Fleming transferred several spores to a dish containing agar
and left them for four or five days to germinate at room temperature. He
soon obtained a colony of the mould similar to the first one. Then he
planted in the same agar different bacteria in isolated streaks, forming, as
it were, the radii of a circle with the mould as centre. After incubation,
he noticed that certain microbes survived in close proximity to the fungus —
the streptococci, the staphylococci and the diphtheria bacillus, for
instance, whereas the typhoid and influenza bacilli were not affected in the
same way.

The discovery was becoming tremendously interesting. Unlike
lysozyme, which acted more especially upon the inoffensive microbes, this
mould seemed to produce a substance which could inhibit the growth of
microbes which caused some of the most serious diseases. It might,
therefore, have an immense therapeutic value. 'Here,' said Fleming, 'it
looks as though we have got a mould that can do something useful.' He
cultivated hispenicilliumin
a larger receptacle containing a nutritive broth. A thick, soft, pock-marked
mass, at first white, then green, then black, covered the surface. At first
the broth remained clear. After several days, the liquid assumed a vivid
yellow colour. What mattered now was to find out whether this liquid also
possessed the bactericidal properties of the mould.

The methods perfected in 1922 for lysozyme suited Fleming's
purpose admirably. He hollowed out a gutter in a dish of agar, and filled it
with a mixture of agar and the yellow liquid. Then microbes were planted in
streaks, perpendicularly to the gutter, up to the very edge of the dish. The
liquid appeared to be just as active as the original mould. The same
microbes were affected. There was therefore in the broth a bactericidal (or
bacteriostatic) substance produced by the mould. How great a strength did it
have? Fleming experimented with weaker and weaker solutions.— a 20th, a
40th, a 200th, a 500th. Even this last still arrested the development of the
staphylococci. The mysterious substance contained in the golden liquid
appeared to be endowed with quite extraordinary power. Fleming at that time
had no means of knowing that the proportion of the active substance in the
'juice' was scarcely more than one in a million. The proportion of gold in
the sea is greater than that.

It was important now to identify the mould. There are
thousands of moulds. Fleming's knowledge of mycology (the science of fungi)
was no more than elementary. He turned to his books, rummaged about in them,
and decided that the substance in question was a penicillium of the genuschrysogenum.
There happened just then to be at St Mary's a young Irish mycologist, C. J.
La Touche, who was assisting Freeman in his researches into asthma. Freeman
had got hold of him because a Dutch research-worker had put forward the
theory that many cases of asthma among those living in damp rooms were due
to moulds. La Touche was a sensitive individual who found the restless
atmosphere of the Inoculation Department little to his liking. But he had
made his colleagues aware of the importance of moulds, and they had
affectionately nicknamed him 'Old Mouldy'.

Fleming showed his fungus to La Touche who, after studying
it, decided that it was thepenicillium
rubrum.
The bacteriologist deferred to the expert and in his first paper on the
subject gave to his mould the name prescribed by La Touche. Two years later,
the famous American mycologist, Thom, identified the fungus as apenicillium
notatum(close
to thechrysogenumwhich
had been Fleming's first diagnosis). La Touche very graciously wrote to
Fleming, apologizing for having misled him. Fleming learned from Thorn's
book that thepenicillium
notatumhad
been originally recognized by a Swedish chemist, Westling, on a specimen of
decayed hyssop. This reminded Fleming the Covenanter, of Psalm 51: 'Purge me
with hyssop and I shall be clean' — the first known reference to penicillin.

Meanwhile, his experiments on the bactericidal action of the
liquid had convinced him that he was in the presence of a phenomenon of
antibiosis. The mould, a rudimentary living creature, produced a substance
which killed other living creatures, microbes. The peaceful co-existence of
the two species was not possible.

That living creatures could be caught up in a vital and
murderous struggle, the spectacle presented by the world had always proved.
They squabble over food, air and living-space. Sometimes they complement
each other, the one providing what the other lacks, and, when that happens,
a shared life, a 'symbiosis5is
possible. More often, however, proximity is fatal to one of them. In 1889
the Frenchman, Vuillemin, had for the first time employed the word
'antibiosis5, defining it thus: 'When two living bodies are
closely united, and one of the two exercises a destructive action on a more
or less extensive portion of the other, then we can say that "antibiosis"
exists.'

A striking example is that of all the infectious microbes
which are ceaselessly being emptied into water and soil. Most of them do not
survive, and this must needs be so, since, otherwise, neither men nor
animals could live at all. What is it that destroys these microbes? To a
very great extent, the sun, but also the action of other microbes which are
inoffensive, or even beneficial, to human beings. There are ancient Greek
texts which point out that certain epidemics cause the disappearance of
other ailments.

In Lister's Commonplace-Books (now in the library of the
Royal College of Surgeons), we find under the date November 25th, 1871, the
following observation: in a glass tube containing urine, Lister noticed the
presence of numerous bacteria, but also of some granular filaments which he
recognized as mould. Seeing that the bacteria seemed to be in poor
condition, he made several experiments for the purpose of determining
whether the growth of mould had the effect of making the liquid an
unfavourable medium for bacteria. These experiments were inconclusive and he
abandoned them. But he had noted that the presence of a soft mass (which he
thought waspenicillium
glaucum)on
the surface of the tube 'was making the bacteria completely immobile and
languid'.

He supposed that what was happening was a competitive
struggle for oxygen, the, penicillium absorbing that contained in the broth
and blocking the surface.

In 1877, Pasteur and Joubert had noticed that the anthrax
bacillus, when injected at the same time as inoffensive bacteria, produces
no infection of the animal. There, again, an antagonism is set up, and the
anthrax bacillus is vanquished.cIn
the inferior organisms,' Pasteur wrote, 'still more than in the great animal
and vegetable species, life hinders life. A liquid invaded by an organized
ferment, or by an aerobe, makes it difficult for an inferior organism to
multiply...' Farther on, having pointed out that a common bacterium
introduced into urine at the same time as the bacterium of anthrax prevents
the development of the latter, he adds: It is a remarkable thing that this
same phenomenon occurs in the bodies of those animals which are most prone
to contract anthrax, and we are led to the surprising conclusion that one
can introduce a profusion of the anthrax bacterium into an animal without
the latter contracting the disease; all that is needed is to add common
bacteria to the liquid which holds the bacterium of anthrax in suspension.
These facts may, perhaps, justify the greatest hopes from the therapeutic
point of view.'1

In 1897, Dr Duchesne, of Lyon, gave to his thesis (inspired
by Professor Gabriel Roux) the title:Contribution
d Vetude de la concurrence vitale chez les micro-organismes. Antagonisme
entre les moisissures et les microbes.
Tt is to be hoped', he concluded,cthat
if we pursue the study of biological rivalry between moulds and microbes, we
may, perhaps, succeed in discovering still other facts which may be directly
applicable to therapeutic science.' In this case, too, the search was not
continued.

We see, therefore, that antibiosis was already a known
phenomenon. But in 1928 the 'climate' of the scientific world was not the idea of penicillin, but he had the wrong mould, or the
wrong bacteria, or both. If Fate had been kind to him, medical history might
have been changed, and Lister might have lived to see what he had always
been looking for - a non-poisonous antiseptic. From the time of Pasteur and
Lister workers have been trying to kill one microbe with another. The idea
was there but the performance had to wait until Fortune decreed that a mould
spore should contaminate one of my cultures, and then for a few years more,
until chemists busied themselves with the products of this same mould to
give us pure penicillin. Lister would indeed have rejoiced to have had such
a thing.'favourable
to research along those lines. In fact, the reverse is true. All former
experiments had demonstrated that every substance fatal to microbesalsodestroyed
the tissues of the human body. This seemed almost self-evident. Why should a
substance which was poisonous for certain living cellsnotbe
so, as well, for others, no less delicate?

cThe fact', said
Fleming, 'that bacterial antagonisms were so common and well known hindered
rather than helped the initiation of the study of antibiotics as we know it
today.' Such facts no longer produced the least excitement, and gave birth
to no hope of a new therapeutic development. More especially was the
atmosphere hostile in Wright's department. The Chief was convinced that the
only means of helping the natural defences of the body was still
immunization. Fleming himself had shown by a brilliant series of experiments
that all the antiseptics had proved abortive. He had discovered a natural
defence, till then unknown — lysozyme. He had tried to increase its
concentration in the blood, but without success. Outside the world of the
greater parasites (trypanosomes, spirochaetes), Ehrlich's 'magic bullet'
remained a dream. Wright could say again, as he had said in 1912, that 'the
chemotherapy of human bacterial infections will never be possible ...'

Fleming, an observer without preconceived ideas, did,
however, see a flicker of hope in his 'mould juice'. Might not the substance
for which he had been looking all through his working life be found there?
Though that distant flicker was, as yet, feeble, he decided to neglect
nothing which might enable him to achieve success. He gave up all other work
to concentrate on this research.

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